The potential to ‘repurpose’ familiar drugs to fight cancer rather than pour billions into novel therapies is exciting scientists here and overseas.
It’s a concept that ticks all the boxes in our innately thrifty Kiwi mentality: dust off an old drug, experiment a little, and presto, you’ve found a cure cancer. Not only can it shave billions off the development cost of novel therapies, it uses established mechanisms to fix a modern scourge – even if treating cancer was not what the drug was invented for.
Metformin, thalidomide, aspirin, tricyclics and statins are familiar drugs developed for other purposes whose potential to treat certain cancers has either already been shown or is being explored in New Zealand and overseas. Some of these drugs had severely tainted reputations; we might have assumed they’d been consigned to the dustbin.
New cancer medicines mostly follow years of testing and clinical trials, and have price tags to match – leaving families with desperate decisions to make about whether to sell the house to pay for therapies that may not work. And in New Zealand, Pharmac funding for novel cancer treatments such as immunotherapy and other drugs is notoriously limited, especially compared with the US, the UK and Australia.
Established drugs, on the other hand, have already undergone thorough testing and have well-established safety profiles. Conducting research on them is cheaper, because they are off patent, and takes less time.
It’s fascinating to think these low-cost drugs might play a role in extending life after a cancer diagnosis.
Metformin was invented 100 years ago and is still used to treat type 2 diabetes. Its potential for cancer prevention and treatment – particularly in inhibiting tumour growth in endometrial, breast and prostate cancers – is the subject of ongoing research.
Thalidomide was launched as a sleeping pill in the mid 1950s but quickly gained popularity with pregnant women as a treatment for morning sickness. By the early 60s, it was synonymous with birth deformities and withdrawn from the market. But in the 1990s, its potential to counter angiogenesis – in which new blood vessels formed from existing ones feed tumours – attracted renewed interest after a chance discovery by an American researcher. In 2006, it was cleared for use in treating the blood cancer multiple myeloma and became the standard treatment. It’s since been replaced by more potent derivatives, such as lenalidomide and pomalidomide, which have fewer side effects and better results.
About 450 new cases of multiple myeloma are diagnosed in New Zealand each year. It can’t be cured but Auckland haematologist Dr Rodger Tiedemann says drugs like lenalidomide can extend life by 5-10 years.
Aspirin a day?
The blood-thinning effect of the painkiller aspirin – launched in 1897 – gave it off-label favour in the 1960s for its potential to reduce heart attacks and strokes. Low-dose aspirin became a standard part of the treatment plan for many patients with cardiovascular disease. But it is notorious for adverse effects including nausea and stomach bleeds, and it is no longer recommended for children due to potentially fatal side effects.
But about 15 years ago, French researchers found it might help to prevent bowel cancer. News of this breakthrough led to a rush of patients seeking a daily dose of aspirin from their GPs to ward off one of this country’s most common cancers – only to be stopped at the door by doctors who would rather their patients didn’t succumb to gastrointestinal bleeds.
Dr Luke Bradford, medical director of the Royal New Zealand College of General Practitioners, says taking aspirin regularly doubles the risk of gastrointestinal bleeding. “Benefits have to outweigh risks,” he says. “The first rule of medicine is first do no harm.”
Tricyclics such as amitriptyline and doxepin were developed as a treatment for depression, but unfortunate side effects and risks soon became apparent. The 1980s saw the rise of SSRIs (selective serotonin reuptake inhibitors such as Prozac), and depression sufferers gratefully switched. But amitriptyline, nortriptyline and other tricyclics continue to be used for a wide range of conditions, from bed-wetting and anxiety to migraine and post-traumatic stress disorder.
In recent decades, growing evidence that nerves play a role in cancer development saw tricyclics re-evaluated not only for their potential to treat cancer-related pain but their possible use to block molecular pathways used by cancer cells for tumour growth and promotion. Clinical trials, however, have been limited.
Statins
Statins are a class of drugs introduced to lower patients’ LDL cholesterol levels; the first, lovastatin, was approved in 1987. They have been revolutionary in cutting rates of heart attack and stroke throughout the world.
Now, though, their potential to curb cancers when used in conjunction with conventional cancer treatment is the topic of much research here and overseas.
Should you ask your GP for statins if you have breast cancer? You might think so if you read a paper on statins and breast cancer by Auckland University PhD student Oliver Scott. His retrospective observational study looked at about 15,000 New Zealand women diagnosed with breast cancer between 2007 and 2016.
About 27% of the cohort were on a statin after they were diagnosed, and results showed they were less likely to die of breast cancer within the follow-up period. This was particularly true for about 700 women with stage 4 cancer, who had a 35% reduced risk of death from breast cancer within the follow-up period of 1.77 years.
Statin use also showed benefit for post-menopausal women (10,202 in the study) who were 26% less likely to die within the median follow-up period of 41/2 years, and women with oestrogen receptor-positive breast cancer, who had a 23% reduced risk.
But, as Scott says, no one would make clinical recommendations based on an observational study – too many other factors could have influenced the results.
Even so, it was enough to excite interest from the New Zealand Breast Cancer Foundation. Its research manager, Adele Gautier, says the study offers some interesting data that echo other results showing benefit from statins.
Though it’s unlikely we’ll see new guidelines recommending statins any time soon, Gautier says for women with breast cancer where options are limited, it might be enough for them to discuss statins with their doctor.
“It’s really fascinating to think these very low-cost drugs, that are very well tolerated and have quite manageable side effects for most people, might play a role in extending life after a cancer diagnosis,” she says, pointing to studies indicating metformin’s potential to counter metastatic breast cancer.
The College of GPs’ Bradford says findings to date are certainly not enough to start all patients on metformin or statins to prevent cancer, but he suggests a case-by-case approach may be merited.
“I suspect a secondary prevention – ie, patients who have had cancer and they don’t want it to come back – that would be a much more understanding conversation that we could have with patients. The evidence is a bit stronger on that.”
Long, slow game
The wheels of progress in international research turn slowly, especially for repurposing drugs, as the large pharmaceutical companies appear to have little enthusiasm for funding clinical trials of unsexy old drugs that have come off patent. Funding from other sources is limited.
Many studies, possibly underpowered from the start, languish in dusty corners of the internet. They show mixed results, and there’s been no real momentum to get gold-standard testing under way.
Yet, now is a good time to push forward, says Dr Clint Gray, director of Wellington independent research institute Gillies McIndoe.
Bringing a new drug to market can take 15 years, whereas a repurposed drug may take only a third of that time, he says. They should be part of the mix because of the vast cost of new drugs, which puts them out of reach of most people privately and stretches public health budgets to breaking point.
Gillies McIndoe specialises in research involving repurposed drugs. Founded by Dr Swee Tan, it enjoyed early success using a blood pressure medication, captopril, for treating strawberry birthmarks, usually benign tumours.
As the Listener reported in January 2022, Tan then turned his attention to glioblastoma, the most common and aggressive form of brain cancer, which accounts for most of the 370 cases in this country each year. In a small phase I trial, he used a cocktail of old drugs that included aspirin, metformin, an anti-inflammatory and the beta-blocker propranolol. Results were positive: the 17 patients had a median survival time of 19.9 months – more than five months longer than with conventional treatments.
Although this was not conclusive, recruitment of 75 patients for Tan’s phase II trial is now underway in the hope the same trend emerges. Results are expected in 2026-27.
A cocktail of remedies
Freya Weth, a PhD student at Gillies McIndoe, has also taken up the torch, having devoted the last 21/2 years to trying to isolate four drugs that might work in combination against glioblastoma. Her work is about understanding the molecular pathways involved in cancer stem cells and the mechanisms of different drugs that may improve or create new treatments for glioblastoma. She started off with 32 drugs and is now down to four that all target similar pathways. The four remain a closely guarded secret until her research is published later this year.
Weth says combining different drugs must be the focus now because there’s no point looking for a silver bullet – the idea that one drug will suddenly stop cancer in its tracks.
In a 2023 paper, published in the British Journal of Cancer, Weth as lead researcher gives the example of thalidomide for multiple myeloma. The response rate using thalidomide for patients was 25-35%, but when used with steroids, trials showed the response rate grew to 50%, and 70% when combined with steroids and an alkylating agent such as the chemotherapy drug melphalan.
“Combination therapy therefore may provide cytotoxic [destructive] effects on cancer cells while simultaneously reducing their harmful effects on normal cells,” the authors say.
The paper looked at research on drug repurposing around the world and summarised that the cost of treatment with new cancer drugs was prohibitive and sometimes offered only modest improvements in life-expectancy or survival rates.
Such new drugs not only put a burden on society but stifled development of equally effective but more affordable alternatives, the authors said. “It takes approximately 13 to 15 years and costs around US$2-3 billion to bring a novel drug to the market, [whereas] repurposing a drug is estimated to take only 6.5 years and cost an average of $300 million.”
Not there yet
The big problem is that many trials using repurposed drugs for cancer have produced mixed results. Of the 100-plus studies Weth looked at, many showed little effect. She believes this is at least partly due to a lack of pre-clinical research, such as gathering data or testing drug synergy – where two or more drugs work together for more effect than their individual parts.
Dr Chris Jackson, professor of cancer medicine at the University of Otago, says it’s still far too early to get excited about things like metformin or statins for curing cancer. The former medical director of the Cancer Society says large studies that look at people over decades have come up with some interesting observations, but when theories have been tested in intervention studies, they fail. An example, he says, is the idea that people who took aspirin were less likely to get colon cancer.
“In fact, we did do a study called the ASCOLT study, where we looked at aspirin after a bowel cancer operation to see if it reduced the rates of cancer coming back, and it didn’t. So, while the observation study was positive, the intervention study was negative.”
But, adds Jackson, “Excitingly, though, on that study, we found patients with a particular mutation in their tumour called PI3K are highly sensitive to aspirin, and they appear to be the group that benefits. So we wouldn’t have found that out if we hadn’t done the study.”
Likewise, researchers have found vitamin D alongside other drugs is a helpful therapy in people with advanced bowel cancer, so Jackson always prescribes vitamin D for patients with stage 4 bowel cancer. A gold-standard study showed people taking daily vitamin D had a slower growth of metastatic bowel cancer than people who took a placebo.
Would he recommend vitamin D to help prevent bowel cancer occurring? No, because the data is just not there. Neither would he recommend vitamin C for bowel cancer and definitely not vitamin A: a US study showed vitamin A in lung cancer patients worsened outcomes.
“So just because you’ve got a vitamin or a natural compound or an old drug doesn’t mean it’s either active or harmless. My only message really is let’s do the trials, because that’s the way we work things out and we make sure things are doing well.”
He rejects the assertion that lack of funding from pharmaceutical companies stands in the way of robust research. In New Zealand, the government-funded Health Research Council funds such studies and it ensures they undergo strict peer review and quality control. “A well-run clinical trial is a totally different beast to a back-of-the-envelope, Excel spreadsheet clinical trial.”
However, if patients ask to try a certain vitamin or drug, – say, a statin – Jackson says he wouldn’t stand in their way. “What I do say to people is there’s no clear evidence in a randomised sense that they’re actually helpful. But equally, it’s not worth having a fight with patients about it, because people are usually in the situation where they want to try anything.”
Statins for rectal cancer
In what Waikato University associate professor Michael Jameson describes as a frustrating exercise, his phase II trial looking at statins for rectal cancer came tantalisingly close to showing a statistically significant result but not close enough.
The trial, which added simvastatin to patients’ chemotherapy and radiation regimes, showed a 12% increase in disease-free survival three years after treatment. But it was let down by low recruitment of patients, partly due to Covid disruptions.
Instead of the 222 patients sought, only 135 were signed up. “So, the parlance we would use is that there is a trend to more people being alive and well three years on from starting treatment if they had a statin than if they didn’t. [But] it wasn’t a statistically significant increase.”
Having spent a $1.4 million Health Research Council grant on the trial, Jameson is disappointed, but now has hopes pinned on a trial at Tata Memorial Hospital, in Mumbai, India, of 216 patients using another statin, rosuvastatin. Early data are expected by the end of the year.
Jameson says it’s hoped results from both trials can be pooled. With a total of 350 patients, researchers may be able to show significant benefit. “We would still need to go on to do a much larger study, but we’d get a lot more people around the world interested in doing that.”
Would he recommend statins now for anyone with rectal cancer? No. “Statins are not harmless. It’s important to be aware of that.” But if you were already taking one, stay on it, he says. That goes for metformin too, if you’re diabetic. “These things may benefit.”
“While the general outcome appears to be better for people who are taking statins when they have bowel cancer, it’s all mixed up with other things. They’re also not smoking, they drink less, they get more exercise and they eat better. All these other things influence survival from bowel cancer.
“There’s some really interesting and promising research coming out but we’re simply not there yet.”
In the meantime, Jameson is devoting his attention to cimetidine, a drug that hit the market in 1978 to treat stomach ulcers and reduce stomach acid. It’s long since dropped off the shelves but he is leading a study looking at its potential to protect against chemotherapy side effects.
One chemo drug in particular, cisplatin, causes hearing loss in most people undergoing treatment for head and neck cancer. In a pilot study, Jameson’s team has recruited 28 patients looking at the degree of hearing loss three months after chemo to see if cimetidine protected their hearing. Jameson expects to start getting results in the next few months. “If that looks promising then it’s going to open up the potential for a huge range of studies where cisplatin is being used at moderate to high doses across a wide variety of cancers, including in children.”
At the University of Auckland, researchers are looking at cimetidine to see if it can prevent nerve damage in the hands and feet when patients are treated with the chemo drug oxaliplatin, which is generally used for bowel and stomach cancer.
Jameson adds such research could level the playing field in terms of access: “In an age where no new cancer drug comes on the market without costing over $10,000 a month, the repurposing drug thing just is a big leveller of equity of access.”
